PMID- 33096655
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20231019
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 10
IP  - 10
DP  - 2020 Oct 21
TI  - Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson's Disease and 
      Potential Therapeutic Role of 5' Untranslated Region-Directed Small Molecules.
LID - 10.3390/biom10101465 [doi]
LID - 1465
AB  - Alpha-synuclein (alpha-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein 
      alpha SNCA gene. It is the synaptic protein associated with Parkinson's disease 
      (PD) and is the most highly expressed protein in the Lewy bodies associated with 
      PD and other alpha synucleopathies, including Lewy body dementia (LBD) and 
      multiple system atrophy (MSA). Iron deposits are present in the core of Lewy 
      bodies, and there are reports suggesting that divalent metal ions including 
      Cu(2+) and Fe(2+) enhance the aggregation of alpha-Syn. Differential expression of 
      alpha-Syn is associated with alcohol use disorder (AUD), and specific genetic 
      variants contribute to the risk for alcoholism, including alcohol craving. 
      Spliced variants of alpha-Syn, leading to the expression of several shorter forms 
      which are more prone to aggregation, are associated with both PD and AUD, and 
      common transcript variants may be able to predict at-risk populations for some 
      movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD 
      and AUD are associated with liver and brain iron dyshomeostasis. Research over 
      the past decade has shown that alpha-Syn has iron import functions with an ability to 
      oxidize the Fe(3+) form of iron to Fe(2+) to facilitate its entry into cells. Our 
      prior research has identified an iron-responsive element (IRE) in the 5' 
      untranslated region (5'UTR) of alpha-Syn mRNA, and we have used the alpha-Syn 5'UTR to 
      screen for small molecules that modulate its expression in the H4 neuronal cell 
      line. These screens have led us to identify several interesting small molecules 
      capable of both decreasing and increasing alpha-Syn expression and that may have the 
      potential, together with the recently described mesenchymal stem cell therapies, 
      to normalize alpha-Syn expression in different regions of the alcoholic and PD brain.
FAU - Cahill, Catherine M
AU  - Cahill CM
AD  - Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General 
      Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
FAU - Aleyadeh, Rozaleen
AU  - Aleyadeh R
AD  - Weill Cornell Medicine-Qatar, Qatar Foundation, Doha 24144, Qatar.
FAU - Gao, Jin
AU  - Gao J
AD  - Department of Clinical Psychology, Qilu Hospital of Shandong University, Qingdao 
      266011, China.
FAU - Wang, Changning
AU  - Wang C
AD  - Athinoula A. Martinos Center for Biomedical Imaging Massachusetts General 
      Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
FAU - Rogers, Jack T
AU  - Rogers JT
AD  - Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General 
      Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
LA  - eng
GR  - R21 NS059434/NS/NINDS NIH HHS/United States
GR  - R21 NS064853/NS/NINDS NIH HHS/United States
GR  - R21 NS077079/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20201021
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 0 (5' Untranslated Regions)
RN  - 0 (SNCA protein, human)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (alpha-Synuclein)
SB  - IM
MH  - 5' Untranslated Regions/genetics
MH  - Alcoholism/*genetics/pathology/therapy
MH  - Brain/drug effects/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Lewy Bodies/drug effects/metabolism
MH  - Neurons/drug effects/metabolism
MH  - Parkinson Disease/*genetics/pathology
MH  - Small Molecule Libraries/*chemistry/therapeutic use
MH  - alpha-Synuclein/*genetics/therapeutic use
PMC - PMC7589448
OTO - NOTNLM
OT  - alcohol
OT  - alpha synuclein
OT  - iron homeostasis
OT  - small molecules
COIS- The authors declare no conflict of interest.
EDAT- 2020/10/25 06:00
MHDA- 2021/06/24 06:00
PMCR- 2020/10/01
CRDT- 2020/10/24 01:00
PHST- 2020/07/30 00:00 [received]
PHST- 2020/09/28 00:00 [revised]
PHST- 2020/10/09 00:00 [accepted]
PHST- 2020/10/24 01:00 [entrez]
PHST- 2020/10/25 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2020/10/01 00:00 [pmc-release]
AID - biom10101465 [pii]
AID - biomolecules-10-01465 [pii]
AID - 10.3390/biom10101465 [doi]
PST - epublish
SO  - Biomolecules. 2020 Oct 21;10(10):1465. doi: 10.3390/biom10101465.